Edema can be defined as an abnormal accumulation of fluid in the interstices of cells in tissue spaces or in body cavities. It can be caused either by excessive movement of fluid from the vascular system into the tissues or inadequate movement of fluid from the tissues back to the vascular system. The normal interchange of fluid between these two compartments is regulated by the ‘Starling equation’ of tissue fluid, whereby the generation of interstitial fluid depends on the balance of osmotic pressure and hydrostatic pressure acting in opposite directions across the semi-permeable capillary walls. Edema is the result of an imbalance in these forces, which tends to cause abnormal accumulation of fluid in the interstitial spaces.
Clinical manifestations of edema include mild to severe swelling of the body and a gain in body weight. The swelling can be caused either by a generalised (or systemic) increase in extra cellular fluid or due to edematous collections that confined to a localised site. Anasarca, the medical condition for generalised edema, is marked by the swelling of the subcutaneous tissues, while localised edema is normally designated, based on the affected site, such as hydrothorax (excess serous fluid in the spaces between the pleura), hydropericardium (excess fluid in the pericardial sac), hydroperitoneum or ascites (excess fluid in the peritoneal cavity), amongst others.
The composition of the extravascular fluid that accumulates in edema varies according to its etiology. In the case of edema caused by non-inflammatory mechanisms, the fluid (transudate) comprises a relatively low protein concentration and is of less specific gravity, indicating that the endothelium of the affected site is normal. In such cases, the transudate is essentially an ultrafilterate of blood plasma. This kind of non-inflammatory edema is primarily caused by alterations in the hemodynamic forces across the capillary wall and is also known as hemodynamic edema. On the other hand, in the case of edema that is caused by an inflammatory response, the extravascular fluid (exudate) comprises a high concentration of protein, cells and cellular debris and has high specific gravity. This indicates a significant alteration in the normal permeability of the small blood vessels in the affected area.
Edema normally occurs as an important functional manifestation of the pathogenesis of various diseases, but can also occur as result of trauma and injury. Heart failure, cirrhosis of the liver and kidney diseases such as nephrotic syndrome are some of the most common systemic diseases that cause edema. The main mechanisms involved in the development of edema during disease pathogenesis include increased intravascular hydrostatic pressure, impairment in the flow of lymph, inappropriate renal sodium and water retention, reduced plasma osmotic pressure, and increased vascular permeability.
Increase in hydrostatic pressure in the veins results in poor re-absorption of fluids from the tissue, and this imbalance results in edema. The increase in hydrostatic pressure may either occur as a generalised increase in venous pressure or affect only a specific site. A local increase in the hydrostatic pressure may result from impaired venous outflow, which is usually encountered in the lower extremities and is secondary to the development of obstructive thrombosis and varicose veins. The resulting edema is localised in the legs and lower limbs, commonly known as peripheral edema. A generalised increase in venous pressure results in systemic edema, which is commonly observed in the case of congestive heart failure. Specifically, failure of the left side of the heart results in fluid collection in the lungs (alveoli), resulting in pulmonary edema and dyspnea. On the other hand, during failure of the right side of the heart, fluid accumulates in the lower limbs, causing peripheral edema. As the condition progresses or worsens, the upper limbs also swell, and eventually, there is collection of fluid in the peritoneal cavity, which results in an edematous condition known as ascites. It has been observed that causes of edema, which are generalised in the whole body, can cause edema in multiple organs.
Impaired flow of lymph or lymphatic obstruction results in inadequate drainage of interstitial fluid, which consequently causes localised lymphedema. Lymphedema is a common debilitating edematic condition in which excess lymph collects in tissues. It may be caused by an inflammatory or neoplastic obstruction, pressure from a cancer or an enlarged lymph node, destruction of lymph vessels by radiotherapy, or the infiltration of lymphatics by infections such as elephantiasis or filariasis, amongst others.
Excessive retention of sodium and water by the kidneys causes an increase in the volume of intravascular fluid, which eventually increases the hydrostatic pressure and causes edema. Conditions such as acute renal failure or streptococcal glomerulonephritis, amongst others, directly affect normal renal function and cause abnormal salt retention in the body. Apart from this, pathogenesis of several disorders such as congestive heart failure, hypoalbuminemia, etc., activates the renin-angiotensin-aldosterone (RAAS) hormonal system, which promotes sodium and water retention. Hence, edema that is initiated by one mechanism gets complicated by the secondary mechanism of salt and fluid retention. An extra fluid load in the body and the vicious circle of fluid retention further imbalances the pressure gradient across the membranes and results in worsening of the edema.
Decreased plasma osmotic pressure inside the vessels facilitates the movement of fluids towards the interstitial spaces, resulting in edema. Such a decrease in plasma osmotic pressure can be the result of either an excessive loss or reduced synthesis of plasma proteins that are impermeable to the capillary membrane, especially albumins, which primarily contribute to maintain the blood volume. The most important cause of excessive loss of albumin is a kidney disorder known as the nephrotic syndrome, which is characterised by a leaky glomerular basement membrane, and which eventually results in generalised edema. Reduced synthesis of serum proteins, especially albumins (or hypoalbuminemia), occurs in diffuse diseases of the liver, such as cirrhosis, or is associated with malnutrition. In all these instances, the movement of fluid from the intravascular to the interstitial compartment results in a contraction in the volume of plasma, which results in generalised edema-like symptoms such as ascites and peripheral edema, amongst others.
Another important cause for excessive loss of plasma proteins is an increase in the permeability of blood vessels to plasma proteins. This increased permeability causes movement of proteins and cells, such as leukocytes from the circulation to the interstitium. The loss of protein-rich fluid from the plasma reduces the intravascular osmotic pressure and increases the osmotic pressure of the interstitial space, which eventually results in an outflow of fluid from the blood vessels to the interstitium, causing edema. An increase in vascular permeability is one of the main characteristics of the inflammatory response of the body against stimuli, especially in the case of acute inflammation. In fact, edema is one of the main signs of acute inflammation. During inflammation, the chemical factors derived from plasma and triggered by inflammatory stimuli mediate a number of vascular and cellular responses in the affected site. These structural changes in the microvasculature result in increased permeability of the blood vessel membrane, causing movement of plasma proteins and cells, e.g. leukocytes from the circulation to the intersititium, which ultimately results in site-specific edema. Inflammatory edema can be largely attributed to the direct action of histamine, bradykinin and other the substances released. The main mechanisms of increased vascular permeability in inflammation include endothelial cell contraction, junctional retraction, direct injury, leukocyte-dependent leakage, regenerating endothelium, amongst others. Increased fluid filtration towards the interstitium is further enhanced by the arteriolar vasodilator action of the inflammatory mediators, which increases the blood flow, the perfused surface area, capillary hydrostatic pressure, and facilitates edema by other mechanisms as well.
In summary, edema is known as one of the important functional manifestations of the pathogenesis of various diseases. Heart failure, cirrhosis of the liver, nephrotic syndrome, amongst others, are some of the most common systemic diseases that eventually result in edema. Understanding the dynamics of edema and the other related clinical manifestations associated with these diseases is important for deciphering their complete pathology and may also help in developing novel and highly specific diagnostic, therapeutic and preventive strategies towards these diseases.
One objective is to make available novel compounds and methods for the prevention, alleviation or treatment of edema. Other objectives and their associated advantages will become apparent upon study of the description and examples.